Kaposi's sarcoma (KS) continues to be a major medical challenge in HIV-AIDS patients even with the extensive use of highly active antiretroviral therapy. This malignancy can have both psychological and physically debilitating affects that negatively impact quality of life. A variety of treatment approaches are being used but unfortunately effective long term palliation of KS remains difficult to achieve. Photodynamic therapy (PDT) has been used in the treatment of KS and has been reported to be effective in part because the procedure can be repeated and is not associated with either immunosuppressive activity or significant systemic toxicity. However, results from previous PDT clinical trials for KS demonstrated that the procedure has not been optimized and recurrences can occur. We propose a novel exploratory project designed specifically to enhance the local tumoricidal response of PDT using angiogenic inhibitors. This application builds upon our recent discovery that PDT induces overexpression of vascular endothelial growth factor (VEGF) and that angiogenic inhibitors can improve PDT responsiveness in murine carcinomas. We also have new preliminary data documenting that PDT also increases VEGF levels in a human KS xenograft model. We hypothesize that PDT induced expression of VEGF decreases treatment efficacy and that a combined modality approach employing PDT and angiogenic inhibitors will be effective in treating KS without inducing a concomitant increase in normal tissue toxicity. The goal of our R21 application is to determine whether drugs selectively inhibiting various components of VEGF signaling will improve the treatment of human KS tumors using PDT. This will be accomplished through in-vivo analysis of treatment responsiveness of human KS tumors transplanted in nude mice. Anti-angiogenic agents that target VEGF (Avastin), VEGF receptor-2 (DC101), or the receptor tyrosine kinase [ZD6474] will be evaluated in experiments designed to examine tumor and normal tissue response. The overall objective of this research is to obtain translational data justifying a novel clinical approach to improve the efficacy of PDT for treating KS. The successful completion of this objective would result in an improved treatment option for KS that exhibits minimal toxicity and which can be used repeatedly and following chemotherapy and/or radiation therapy. [unreadable] [unreadable] [unreadable]